Keratoderma with woolly hair type 3 is a genetically inherited syndrome characterized by arrhythmogenic right- or biventricular dysplasia with or without woolly hair and diffuse nonepidermolytic palmoplantar keratoderma (PPK). It is exceedingly rare, with only a handful of documented cases in Germany, Lebanon, Pakistan, Italy, and the Alberta Hutterite population.

Keratoderma with woolly hair type 3 is caused by a mutation in the DSC2 gene on chromosome 18, which encodes for desmocollin 2. Desmocollin 2 is a cadherin that plays an essential role in the function of desmosomes found in epithelial cells, cardiomyocytes, and other specialized cell types. Dysfunction results in progressive fibrofatty replacement of the myocardium, increased hair follicle proliferation, and hyperkeratosis induced by mechanical pressure. The DSC2 mutation is inherited in an autosomal dominant manner, but an autosomal recessive inheritance pattern has also been noted in association with the cardiocutaneous phenotype. Desmocollin 2 is one of three isoforms of desmocollin (desmocollin 1, desmocollin 2, and desmocollin 3), but is the only one that is present in cardiac tissue. Compensation by desmocollin 1 and desmocollin 3 in noncardiac tissue results in the mild or absent presentation of cutaneous and hair involvement.

Woolly hair presents as tightly coiled, unusually frizzy, difficult-to-comb hair diffusely on the scalp that is apparent at birth. Palmoplantar hyperkeratosis begins in the first year of life. The keratoderma is usually diffuse and nontransgrediens. The age at which cardiac symptoms appear is variable but can emerge as early as adolescence. Cardiac presentation can range from asymptomatic to mild symptoms (ie, palpitations, syncope) to severe complications (ie, fatal ventricular tachyarrhythmias, heart failure, sudden cardiac death). Arrhythmogenic cardiomyopathy in most reported cases of keratoderma with woolly hair type 3 is limited to the right ventricle. Biventricular involvement can occur but is not seen in all cases. Isolated left ventricular arrhythmogenic cardiomyopathy has not been linked to the DSC2 mutation.